Dengue virus (DENV) is the cause of the acute febrile and debilitating diseases dengue fever and dengue hemorrhagic fever (DHF). These diseases affect an estimated 50 million individuals each year, making a licensed dengue vaccine a global health priority. Four serotypes of DENV, a single stranded RNA virus, infect human populations worldwide but there is currently no effective DENV vaccine. While primary infections of each serotype typically result in a quickly contained illness, a second challenge with a different serotype can lead to lethal complications, in part, due to the presence of harmful cross-reactive antibodies. These issues highlight the imperative of optimizing any vaccine formulation to promote a protective adaptive immune response to all serotypes, avoiding harmful side effects. Mast cells (MC) are present in tissues at the host- environment interface, such as the skin, where DENV-infected mosquitoes deposit virus, and are distributed systemically throughout connective tissues. Although the role of MCs in promoting optimal immunity during bacterial infection is well characterized, MCs are also known for detrimental contributions to certain inflammatory conditions. Few studies have examined interactions of MCs with viral infections and DENV infection, specifically. Our previous work and preliminary data reveal that MCs strongly react to DENV and can limit the spread of DENV infection when localized in the skin. However, preliminary data also suggest that when DENV virus particles are present in large numbers, systemically, MCs can contribute to vascular leakage, particularly when MCs are sensitized with heterologous anti-DENV antibodies during secondary infection. Here, we propose to extend these observations to investigate the role of MCs in mobilizing protective immunity against DENV to primary or homologous secondary challenges and to examine their contribution, if any, to complications of secondary challenge with a different serotype. Furthermore, by capitalizing on the capacity of MCs to offer early protection from DENV, we may prevent the establishment of systemic infection. MC activators, when incorporated in vaccines, can serve as potent adjuvants by evoking a powerful immune response. Therefore, finally, we propose to develop a novel vaccine strategy that selectively harnesses the MCs capacity to amplify and augment protective adaptive immune responses to generate high affinity antibodies and productive cellular immunity simultaneously against all DENV serotypes.